Breast cancers are typically Stage-1 (<2cm) at presentation, which limits the use of common functional imaging modalities in the work-up of early breast cancer because of limited spatial resolution. At the University of Washington (UW), positron emission tomography (PET) has been used with success as a biomarker to provide prognostic information about and evaluate therapy in locally advanced breast cancers. Our long-term goal in this project is to expand the use of PET as a biomarker for treatment response in breast cancer. This will more specifically direct therapy selection, resulting in improved outcomes and preventing cost and side effects associated with ineffective therapy. High resolution quantitatively accurate PET will be integrated with clinical mammography or tomosynthesis and biopsy-guidance methods to achieve this goal. The aims of this project are: (1) design a PET detector unit using monolithic scintillation crystals coupled to Geiger-mode silicon photo-multipliers; (2) build and test a fully tomographic PET scanner that mates to a conventional mammography/tomosynthesis gantry for combined PET and x-ray imaging within the mammography suite; (3) integrate the PET scanner with clinical mammography or tomosynthesis equipment and biopsy guidance; (4) characterize the prototype and test it with pilot patient studies. This will be a collaboration between the UW and the GE Global Research Center. Using monolithic crystal detector methodologies developed at UW, the basic detector development will be lead by GRC with close involvement of UW co-investigators; GRC team will also lead systems integration onto mammography equipment; the overall system performance and clinical implementation will be spearheaded at the UW. The result of this work will be a dedicated breast PET system that operates in a mammography suite; initially used to expand therapy evaluation trials currently underway for advanced breast cancer using clinical PET. The device will enable investigation of using PET as a biomarker in early stage disease, including the use of diverse PET tracers available from the UW Radiochemistry cyclotron. It will be a prototype for a commercial-ready design that can be replicated for deployment at other institutions. The proposed system will provide a clinical tool to effectively investigate possible uses of PET to fight early-stage breast cancer.